Nanotechnology has the potential to significantly impact the development of small animal models of cancer including models to test new antineoplastic therapies. In this project we will develop mouse tumor xenoqraft models that will allow us to test if we can combine both tissue/serum nanosensor based proteomic analysis and molecular imaging with targeted fluorescent quantum dots to predict and monitor treatment response with specific therapies. These models are important to the overall vision of this CCNE-TR for which would like to eventually utilize ex vivo nanosensors and in vivo molecular imaging in cancer patients for improving how we predict and monitor response to therapies. In Aim 1 we will optimize small animal optical imaging instrumentation for imaging quantum dots and also work with General Electric Global Research to develop and test a new frequency domain optical imaging instrument. In Aim 2 we will utilize biologically targeted quantum dots developed in Projects 5 and 6 to image tumors in living mice. We will proceed systematically from targeting one known tumor cell surface antigen (CD20 in our lymphoma xenograft model) to targeting several known tumor cell surface antigens (her2/her3/PSCA in our prostate cancer model), before expanding our target range to neovascularization (avp3 Integrin) and extracellular matrix targets (Matrix metalloproteinase 2, MMP2). In Aim 3 we will develop mouse models of lymphoma for testing antineoplastic therapies in order to study changes in proteins at the cell membrane, in the secretome, and in serum. Cell surface and serum proteome will be analyzed by Solid Phase Extraction of Glycoproteins (SPEC) and Liquid Chromatography Mass Spectrometry (SPEG/MS), whereas secretome will be assessed by biotin capture and subsequent cellular functional profiling array for changes that are predictive of response to therapy. We will test two lymphoma therapy models, one xenograft model for human lymphoma mimicking response vs. resistance to Rituxan therapy, and a mouse pre-clinical model of response vs. resistance to targeted inactivation of the MYC oncogene. In Aim 4 we will test a mouse cancer model using the results from the previous three aims in order to determine the utility of integrating ex vivo and in vivo nanotechnologies to determine protein changes in the tissue/serum and to image molecular changes pre and post-therapy. The significance of this work is that it should help set the foundation for using ex vivo nanosensors in clinical trials, to allow development of novel molecular imaging probes for clinical trials, and to improve drug testing in small animal cancer models. This should lead to marked improvement in predicting and monitoring response to therapy in cancer patients.